Pharmaceutical compositions containing piperazine derivatives in the treatment of pain

ABSTRACT

IN WHICH R is CF3, OCF3, or -SCF3 and their salts have interesting anti-inflammatory and, especially analgesic properties.   Piperazines of the formula:

ilnited States Patent I19] Najer et al.

] Assignee: Synthelabo, Paris, France Filed: Apr. 2, 1974 Appl. No.: 457,201

[30] Foreign Application Priority Data Apr. 5, 1973 France 73.12278 Mar. 4, 1974 France 74.07276 [52] US. Cl. 424/250 Dec. 31, I974 [51] Int. Cl A6lk 27/00 [58] Field of Search 424/250 Primary E.raminerStanley J Friedman Artorney, Agent, or FirmArmstrong, Nikaido &

Wegner [57] ABSTRACT Piperazines 0f the formula:

in which R is CF OCF or -SCF and their salts have interesting anti-inflammatory and, especially analgesic properties.

16 Claims, N0 Drawings PHARMACEUTICAL COMPOSITIONS CONTAINING PIPERAZINE DERIVATIVES IN THE TREATMENT OF PAIN The present invention relates to pharmaceutical compositions containing piperazine derivatives.

In French application No. 72/15,642 of 3rd May, 1972, now US. Pat. No. 2,186,237 of Jan. 11,, 1974, compounds are described having the formula:

where are used as intermediates in the synthesis of medicines.

lt has now been found that such compounds themselves possess valuable pharmacological properties, especially when administered as a salt, e.g., as mentioned below, or with phenylbutazone or hydroxyphenylbutazone.

The present invention accordingly provides pharmaceutical compositions containing, as active principle, an effective amount of a piperazine of the formula:

in which R is CF OCF or SCF or an addition salt thereof with a pharmaceutically tolerated acid, especially hydrochloric acid, benzoic acid, salicylic acid, and 2-acetoxy-benzoic acid.

The compounds of formula 1 can be prepared by reacting a compound of the formula:

where R is as hereinbefore defined, with a halogenated alcohol of formula X CH CH OH or with ethylene oxide.

The reaction with the halogenated alcohol is preferably carried out in a solvent, especially an alcohol or a ketone, at the reflux temperature in the presence of an acceptor for a hydrogen halide. The rection with ethylene oxide is preferably carried out in an alcohol, at a temperature from 40 to 100C.

The aminoalcohols of formula (1) thus obtained can be converted into their acid addition salts by reaction, in an organic solvent, with a pharmaceutically tolerated acid, such as one of those mentioned above, followed by evaporation of the solvent under reduced pressure. The organic solvent can be, for example, dichloromethane or methanol.

Examples 1 to 4 illustrate the preparation of the aminoalcohols of formula (I) and Examples 5 to 7 the preparation of their acid addition salts.

EXAMPLE 1 2-bromoethanol and 127.2 g (1.2 mols) of sodium carbonate in 700 ml of ethanol is heated at the reflux tem-' Analysis: c u mu o (M.W. 274.287)

Calculated "/2 C 56.93 H 6.25 N 10.21 Found it 56.85 6.29 10.17

EXAMPLE 2 2-(4-m-Trifluoromethylphenyl-piperazino)-ethanol 23 'g (0.1 mol) of 1-m-trifluoromethylphenylpiperazine are introduced into a pressure apparatus,

cooled by a bath of ice and salt. 4.85 g (0.11 mol) of ethylene oxide which has been cooled beforehand are then added, followed by 15 ml of 98percent methanol. The apparatus is closed and the mixture is heated at 60C. for 8 hours. The mixture is then cooled, and the excess ethylene oxide followed by the methanol are evaporated. The residue is distilled under reduced pres sure. 22.8 g (yield 83.6 percent) of 2-(4-mtrifluoromethylphenyl-piperazino)-ethan0l, similar to the product of Example 1, are obtained, b.p. 142-143C/0.0l mm.Hg.

EXAMPLE 3 2-(4-m-Trifluoromethylthiophenyl-piperazino-ethanol 26.3 g (0.10 mol) of 1-m-trifluoromethylthiophenylpiperazine, 12.2 g (0.15 mol) of 2-chloro-ethanol, 15.9 g (0.15 mol) of sodium carbonate and 300 ml of ethanol are introduced into a flask equipped with a stirrer. After the suspension has been heated for 6 hours at the reflux temperature, the solid phase is removed by filtering the boiling reaction mixture. The ethanol is evaporated from the filtrate, the residue is taken up in diethyl ether, a slight amount of insoluble matter is filtered off, and the other solution is washed with water and'dried over magnesium sulphate. The ether is driven off and the product is distilled under reduced pressure. 26.85 g (yield 87.6 percent) of 2-(4-m-trifluoromethylthiophenyl-piperazino)-ethanol are thus obtained b.p. 182C/0.01 mm.Hg.

Analysis: C H EN OS (M.W. 306.351)

Calculated C 50.97 H 5.59 N 9.14 Found z 50.82 5.67 9.08

EXAMPLE 4 2-(4-m-Trifluoromethoxyphenyl-piperazino)-ethanol 28.6 g (0.116 mol) of l-m-trifluoromethoxyphenylpiperazine, 16.8 g (0.135 mol) of 2-bromo-ethanol,

14.3 g (0.135 mol) of sodium carbonate and 300 ml of 4-methyl-2- pentanone are mixed. The mixture is heated at the reflux temperature for 5 hours, with stirring. The boiling reaction mixture is filtered to remove the inorganic salts, the solvent is driven off from the filtrate, and the product is distilled under reduced pressure. The reaction of the distillate which passes over at 155 to 158C under a presusre of 0.01 mm.Hg is collected. 22.1 g (yield 65 percent) of 2-(4-mtrifluoromethoxyphenyl-piperazino)-ethanol are thus obtained.

Analysis: c,,11,,F,N,o (M.W. 290.287)

Calculated C 53.79 H 5.90 N 9.65 Found 53.68 5.97 9.58

EXAMPLE 5 2-(4-m-Trifluoromethylphenyl-piperazino)-ethanol monohydrochloride. (Code number: SLB 092) 13.7 g (0.05 mol) of 2-(4-m-trifluoromethylphenylpiperazino)-ethanol, produced according to Example 1 or 2, are dissolved in 100 ml of dichloromethane, and 12.5 ml of a 4N solution of hydrogen chloride in ethanol are then added slowly with stirring. The solvents are percent) of 2-(4-m-trifluoromethylphenyl-piperazino)- ethanol mono-2-acetoxy-benzoate, m.p. 95C., are thus obtained.

Analysis: C H F N O (M.W. 454.449)

Calculated C 58.14 H 5.54 N 6.28 Found 57.92 5.57 6.14 58.10 5.59 6.07

Acute toxicity The tests were carried out on Swiss mice of the CD1 strain, of both sexes, and the 50 percent lethal doses were calculated graphically.

Analgesic effect evaporated under reduced pressure. The residue is dis- I solved in boiling 2-propanol, the solution is cooled on This effect was investigated in accordance with two ice, and the hydrochloride which has formed is filtered conventional experimental procedures. off and dried. 13.2 g (yield 85.2 percent) of 2-(4-m- :1. Effect against pain induced, in CD1 mice, by the trifluoromethylphenyl-piperazino)-ethanol monohyintraperitoneal injection of acetic acid, in accordance drochloride, mp. 224C, are thus obtained. with the method described by Koster and colleagues Analysis: C,,H,,C1F,N,o (M.W. 310.748)

Calculated C 50.25 H 5.84 N 9.01 Cl11.48 Found 50.32 5.93 9.08 11.21 50.18 6.10 8.94 11.32

EXAMPLE 6 (Fed. Proc., 1959, 18, 42) and modified by Peterfalvi, 2 (4 m Trifluommethylthiopheny] piperazino) Brancem and colleagues (Med. Pharmacol. exp., 1966, ethanol monohydrochloride. (Code number: SLB 151) 2552i" 7 7.5 ml of a 4N solution of hydrogen chloride in ethanol Test 8 a Plate heated y acetone p are added to a Solution f 2 g 003 mol) f 2 4 40 rred out on CDlmice in accordance with the technique trifluoromethylthiophenyl-piperazino)-ethanol,- proof y and Leimbach Pharm- P- Therapq 1953, duced according to Example 3, in 70 ml of dichloro- 107, methane. The solvents are evaporated and the residue The results obtained in the Koster test, which demonis recrystallized from 2-propanol. 9.25 g of 2-(4-mstrates effects of the peripheral type, show that the actrifluoromethylthiophenyl-piperazino)-ethanol mono- .tivity of the majority of the compounds investigated is hydrochloride, mp. 152C., are thus obtained. very much greater than that of the reference substance.

Analysis: C,,,H,,c11=,N,os (M.W. 342.812)

Calculated 1 c 45.54 H 5.29 N 8.17 c1-10.34 Found 45.67 5.26 8.15 10.57 45.64 5.37 8.14 10.59

EXAMPLE 7 In the heated plate test, all the compounds of the invention possess a much greater activity than the refer- 5 ence substance.

Anti-inflammatory effect The test of oedema induced by carragenin in S. J. rats, according to the technique of Winter and colleagues (Proc. Soc. exp. Biol. Med., 1962, 111, 544) was used. The compounds of the invention possess an activity which is lower than that of the reference prodvacuo at ambient temperature. 22.2 g (yield 92.2 uct.

(a) AD 50=50% active dose (dose which reduces the number of contortions induced by acetic acid by 50%) (b) MAD= Mean active dose (dose which increases the reaction time by l%) (c) AD 40= 40% active dose (dose which reduces the volume of the oedema induced by carragenin in the control animals by 40%) These experimental data show that the compounds of the invention possess very marked analgesic properties, greater than those of amidopyrine. They also show a marked dissociation between the analgesic properties and the anti-inflammatory properties, in favour of the first. This dissociation is very valuable in the treatment of specific algias.

The compounds of formula I and their salts can thus be used in human and veterinary medicine, in the treatment of the various pain syndromes. They consequently form the active principles of pharamaceutical compositions wherein they are combined with a compatible carrier so that they can be administeredorally, endorectally or parenterally. These pharmaceutical compositions can also contain other medicinal substances with which the compounds of formula I are pharmaceutically and therapeutically compatible.

For oral administration, any pharmaceutical forms suitable for this method are used, that is to say tablets, dragees, gelatine-coated pills, capsules, cachets and (4-m-trifluoromethylphenyl-piperazino )-ethanol,

drinkable solutions or suspensions, e. g., a syrup or elixir. The unit dose of the compound of formula I is from 20 to 500 mg, and the daily dose may be from 100 to 1,500 mg per day.

For rectal administration, suppositories containing 50 to 1,000 mg of the compound of formula I are used and are administered to the patient at the rate of l to 3 per 24 hours.

For parenteral administration, injectable solutions buffered to the physiological pH are used and are prepared before hand or at the time of use The unit dose is from 25 to 500 mg and the maximum daily dose is 1,000 mg.

We claim:

l. A method of relieving pain which comprises administering to a subject suffering therefrom an effective amount of a piperazine of the formula:

3. A method according to claim 1, in which from 50' to 3,000 mg. of said piperazine is administered rectally. 4. A method according to claim 1, in which from 2 5 to 1,000 mg. of'saidpiperazine is administered parenterally.

5. A method of claim 1, wherein said piperzine is 2- monohydrochloride or itsmono-Z-acetoxy-benzoate.

6. A method of claim 1 wherein said piperazine is 2- (4-m-trifluoromethylthiopenyl-piperazino)-ethanol or its monohydrochloride. 

1. A METHOD OF RELIEVING PAIN WHICH COMPRISES ADMINISTERING TO A SUBJECT SUFFERING THEREFROM AN EFFECTIVE AMOUNT OF A PIPERAZINE OF THE FORMULA:
 2. A method according to claim 1, in which from 100 to 1,500 mg. of said piperazine is administered orally.
 3. A method according to claim 1, in which from 50 to 3,000 mg. of said piperazine is administered rectally.
 4. A method according to claim 1, in which from 25 to 1,000 mg. of said piperazine is administered parenterally.
 5. A method of claim 1, wherein said piperzine is 2-(4-m-trifluoromethylphenyl-piperazino)-ethanol, its monohydrochloride or its mono-2-acetoxy-benzoate.
 6. A method of claim 1 wherein said piperazine is 2-(4-m-trifluoromethylthiopenyl-piperazino)-ethanol or its monohydrochloride. 